Twenty-nine hyperactive boys were randomly assigned to treatment with desipramine (DMI) (n=17) or placebo (n=12) for 14 days in a non-crossover, double-blind study. There was immediate behavioral improvement at Day 3, sustained for two weeks; behavioral improvement did not correlate with plasma concentration of DMI, OH-DMI, or their sum at either Day 3 or 14. There were no untoward side effects; there was a drug-induced increase in pulse and diastolic blood pressure. On drug, urinary excretion of NE, VMA, and MHPG was decreased at both Days 3 and 14. The decreases in both urinary and plasma MHPG showed significant correlations with behavioral improvement during the second week. These data corrobate previous findings on sympathomimetic effects of tricyclics in children and support a nonadrenergic mechanism for mediation of drug effects on behavioral hyperactivity (Attention Deficit Disorder with Hyperactivity).